TP53 Germline Variants Linked With Poor Outcomes in Pediatric ALL

Presence of germline TP53 variants predisposed children to acute lymphoblastic leukemia (ALL) and was associated with adverse outcomes compared with children who did not have these variants, according to the results of a study published in Journal of Clinical Oncology.

“Our findings strongly point to germline TP53 variants—and inherited genetic variation in general—as an important determinant of ALL leukemogenesis and treatment response,” wrote Maoxiang Qian, PhD, of St. Jude Children’s Research Hospital in New York, and colleagues. “Our observation that TP53 risk variants are strongly associated with treatment outcome warrants clinical consideration, in particular, pre-emptive surveillance for second cancers.”

According to the study, recent research has noted germline TP53 variants in childhood hypodiploid ALL. Because germline TP53 variations are the genetic basis of the cancer predisposition condition Li-Fraumeni syndrome, this suggests that childhood hypodiploid ALL may be a manifestation of Li-Fraumeni syndrome.

To investigate this further, Qian and colleagues performed targeting sequencing of TP53 coding regions in 3,801 children from the Children’s Oncology Group frontline ALL clinical trials. TP53 variants were analyzed for their association with ALL presenting features and treatment outcomes.

The researchers identified 49 unique non-silent rare TP53 coding variants in 77 of the 3,801 patients. Of the 49 variants, 22 were classified as pathogenic. TP53 pathogenic variants were five times more common in ALL patients compared with non-ALL controls (odds ratio, 5.2; P < .001).

Those patients found to have TP53 pathogenic variants were significantly older at diagnosis (median age 15.5 vs 7.3 years; P < .001) and were more likely to have hypodiploid ALL (65.4% vs 1.2%; P < .001) compared with children without the variants.

Looking at the relationship with outcomes, the researchers found that presence of these germline variants was associated with significantly worse event-free (HR, 4.2; P < .001) and overall survival (HR, 3.9; P < .001).

Specifically, those children with germline TP53 variants were at a significantly increased risk for diagnosis of a second cancer compared with those without the variants. The 5-year cumulative incidence of second cancer was 25.1% for TP53 variants and 0.7% without (P < .001).

The researchers noted that “as a result of the high risk of treatment failure, patients with hypodiploid ALL frequently undergo hematopoietic stem cell transplantation. The risk of inducing second cancers with total body irradiation–based preparative regimens presents a significant clinical conundrum.”